Energy expenditure can be measured accurately and precisely under laboratory conditisor using either direct calorimetry or respiratory gas analysis. Unfortunately, these methods are not applicable in free-living subjects nor are they very useful in hospitalized subjects because the methods are too restrictive. We have been developing and validating the doubly labeled water method for the measurement of energy expenditure. This method is noninvasive and nonrestrictive. It is ideally suited for measurement of energy expenditure in free-living and hospitalized subjects. Water labeled with the stable isotopes O18 and H2 is given orally. Saliva is collected 3 to 4 hours later for the determination of total body water by isotope dilution. Urine is collected 1 day after the dose and again 5 to 21 days after the dose for the determination of the isotope elimination rates. Because oxygen in CO2 equilibrates with oxygen in body water, the O18 elimination rate measures the CO2 and H2O flux. The H2 elimination rate measures the H2O flux. The difference between the isotope elimination rates is, therefore, a measure of CO2 flux and, therefore, energy expenditure. The doubly labeled water method has been validated in adults. It is accurate to within a few percent and has a relative precision of 4 to 8 percent. Further validations are planned in infants. The doubly labeled water method will be applied in studies to determine the energy requirements of children with inflammatory bowel disease, severe motor disorders, or Prader-Willi syndrome in order to improve the nutritional care of these populations. The method will also be applied in studies of the effect of malnutrition and dietary repletion in order to elicit the factors controlling energy balance. The doubly labeled water method appears to be the first accurate and precise method for measuring energy expenditure in free-living, untrained subject. The development of this method will open new areas of research in human energy metabolism.